Yersinia pestis, the etiologic agent of plague, has been responsible for high mortality in several epidemics throughout human history. There are several thousand reported cases of the disease worldwide annually and an emergence of Y. pestis strains resistant to multiple drugs. Plague has been classified as a re-emerging disease by the World Health Organization and Y. pestis is considered a potential bioweapon owing to its extreme virulence. Despite a need, there are no licensed plague vaccines available in the United States currently. Because of these considerations, we will construct highly attenuated Y. pestis and Y. pseudotuberculosis strains modified to express selected Y. pestis protective antigens at higher than normal levels for use as vaccines. Our studies will focus on evaluating the efficacy of these strains against a high-dose pneumonic and subcutaneous Y. pestis challenge. Attenuated Y. pseudotuberculosis vaccine strains vectoring Y. pestis antigens (LcrV and/or F1) and selected Y. pestis vaccine strains will be evaluated as oral vaccines against high-dose Y. pestis challenges by both pneumonic and bubonic routes of infection. PUBLIC HEALTH RELEVANCE: Y. pestis, the etiologic agent of plague, has been responsible for high mortality in several epidemics throughout human history. There are no licensed plague vaccines available in the United States currently. We will explore using live attenuated Yersinia synthesizing high levels of selected Y. pestis antigens as a vaccine against bubonic and pneumonic plague. These studies will provide us with live attenuated Yersinia vaccine candidates suitable for use in humans and as a zoonotic vaccine suitable for use in rodent baits.